Variable cellular ivacaftor concentrations in people with cystic fibrosis on modulator therapy

The development of CFTR modulators has transformed the care of patients with cystic fibrosis (CF). Although the clinical efficacy of modulators depends on their concentrations in target tissues, the pharmacokinetic properties of these drugs in epithelia are not utilized to guide patient care. We developed assays to quantitate ivacaftor in cells and plasma from patients on modulator therapy, and our analyses revealed that cellular ivacaftor concentrations differ from plasma concentrations measured concurrently, with evidence of in vivo accumulation of ivacaftor in the cells of patients. While the nature of this study is exploratory and limited by a small number of patients, these findings suggest that techniques to measure modulator concentrations in vivo will be essential to interpreting their clinical impact, particularly given the evidence that ivacaftor concentrations influence the activity and stability of restored CFTR protein

Localization of the thyrotropin-releasing hormone gene, Trh , on mouse Chromosome 6

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47026/1/335_2004_Article_BF00355651.pd

Two-domains bulklike Fermi surface of Ag films deposited onto Si(111)-(7x7)

Thick metallic silver films have been deposited onto Si(111)-(7x7) substrates at room temperature. Their electronic properties have been studied by using angle resolved photoelectron spectroscopy (ARPES). In addition to the electronic band dispersion along the high-symmetry directions, the Fermi surface topology of the grown films has been investigated. Using ARPES, the spectral weight distribution at the Fermi level throughout large portions of the reciprocal space has been determined at particular perpendicular electron-momentum values. Systematically, the contours of the Fermi surface of these films reflected a sixfold symmetry instead of the threefold symmetry of Ag single crystal. This loss of symmetry has been attributed to the fact that these films appear to be composed by two sets of domains rotated 60$^o$ from each other. Extra, photoemission features at the Fermi level were also detected, which have been attributed to the presence of surface states and \textit{sp}-quantum states. The dimensionality of the Fermi surface of these films has been analyzed studying the dependence of the Fermi surface contours with the incident photon energy. The behavior of these contours measured at particular points along the Ag $\Gamma$L high-symmetry direction puts forward the three-dimensional character of the electronic structure of the films investigated.Comment: 10 pages, 12 figures, submitted to Physical Review

Transient deformation associated with explosive eruption measured at Masaya volcano (Nicaragua) using Interferometric Synthetic Aperture Radar

Deformation caused by processes within a volcanic conduit are localised, transient, and therefore challenging to measure. However, observations of such deformation are important because they provide insight into conditions preceding explosive activity, and are important for hazard assessment. Here, we present measurements of low magnitude, transient deformation covering an area of ∼4 km2 at Masaya volcano spanning a period of explosive eruptions (30th April - 17th May 2012). Radial uplift of duration 24 days and peak displacements of a few millimetres occurred in the month before the eruption, but switched to subsidence ∼27 days before the onset of the explosive eruption on 30th of April. Uplift resumed during, and continued for ∼16 days after the end of the explosive eruption period. We use a finite element modelling approach to investigate a range of possible source geometries for this deformation, and find that the changes in pressurisation of a conduit 450 m below the surface vent (radius 160 m and length 700 m), surrounded by a halo of brecciated material with a Young’s modulus of 15 GPa, gave a good fit to the InSAR displacements. We propose that the pre-eruptive deformation sequence at Masaya is likely to have been caused by the movement of magma through a constriction within the shallow conduit system. Although measuring displacements associated with conduit processes remains challenging, new high resolution InSAR datasets will increasingly allow the measurement of transient and lower magnitude deformation signals, improving the method’s applicability for observing transitions between volcanic activity characterised by an open and a closed conduit system

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM